PROJECT SUMMARY/ABSTRACT Alcohol use disorder (AUD) is highly prevalent in individuals with bipolar disorder (BD). Co-occurring AUD+BD is associated with significantly poorer clinical outcomes than AUD or BD alone. One approach towards improving AUD+BD treatment is to identify novel medications that target shared neurobiological mechanisms of AUD and BD including dysfunctional reward brain circuitry. Research shows the same circuitry to be activated to various rewards (i.e., food, social reward, and drug cues). AUD and BD individuals both exhibit reward circuitry ?hypersensitivity? albeit to different types of rewards. AUD individuals show heightened activation to alcohol cues relative to other rewards (e.g., monetary, food, and social reward [e.g., happy faces]) whereas BD individuals show increased activation to monetary and social reward. Reward in AUD+BD is in need of investigation; however, alcohol cues may be principally salient due to the ?hijacking? of brain reward system circuitry that emerges through prolonged ethanol exposure; in part, through glutamate and y- aminobutyric acid (GABA) mediated neuroplasticity of the medial prefrontal cortex-nucleus accumbens (mPFC- NAcc) pathway. Animal studies show this pathway modulates the motivational salience of drug stimuli and the expression of drug-seeking behaviors. Medication-induced increase in mPFC-NAcc functional connectivity has been associated with reduced vulnerability to addiction relapse. Published findings by the fellowship sponsor revealed abnormally low glutamate and GABA levels in a medial frontal region including the mPFC in AUD+BD; both were negatively associated with alcohol craving. Pharmacotherapuetic treatment of AUD+BD with medications known to alter levels of glutamate (n-acetylcysteine; NAC) and GABA (gabapentin) may modulate reward function by decreasing activation to alcohol cues and increasing activation to natural rewards (e.g., food and social reward). The proposed fMRI study employs a novel natural rewards task as an add-on to an ongoing 3-week, double-blind, crossover, proof-of-concept study of gabapentin and NAC in AUD+BD. Aim 1 examines whether gabapentin and/or NAC alter relative brain activation to natural rewards versus alcohol cues. Aim 2 examines medication-induced change in task-dependent functional connectivity in the mPFC- NAcc pathway. Gabapentin and NAC are expected to: 1) significantly decrease brain activation to alcohol cues and increase activation to natural rewards, and 2) significantly decrease mPFC-NAcc functional connectivity for alcohol cues while increasing functional connectivity for natural rewards. Exploratory aims include examining associations between Aim 1 activation and alcohol craving and drinking severity. The proposed F32 study is the first to jointly measure pharmacotherapeutic intervention on brain activation to alcohol cues and natural rewards in AUD and/or BD. These methods may be adopted by future addiction treatment outcomes studies attempting to evidence reduction in drug-cue activation and increased activation to natural rewards. !